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PNAS 104 (31): 12843-12848

Copyright © 2007 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / IMMUNOLOGY

TNF-{alpha} suppresses the expression of clock genes by interfering with E-box-mediated transcription

Gionata Cavadini*, Saskia Petrzilka*, Philipp Kohler*, Corinne Jud{dagger}, Irene Tobler{ddagger}, Thomas Birchler*,§, and Adriano Fontana*,§

*Division of Clinical Immunology, University Hospital Zurich, Haeldeliweg 4, CH-8044 Zurich, Switzerland; {dagger}Institute of Biochemistry, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland; and {ddagger}Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 15, 2007

Received for publication February 22, 2007.

Abstract: Production of TNF-{alpha} and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-{alpha} and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-{alpha} on the circadian timing system. TNF-{alpha} is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-{alpha} on clock genes is shared by IL-1beta, but not by IFN-{alpha}, and IL-6. Furthermore, TNF-{alpha} interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-{alpha} is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-{alpha} and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.

Key Words: behavior • circadian rhythms • cytokines • innate immunity


Author contributions: G.C. and S.P. contributed equally to this work; T.B. and A.F. contributed equally to this work; G.C., S.P., I.T., T.B., and A.F. designed research; G.C., S.P., P.K., C.J., T.B., and A.F. performed research; C.J. and I.T. contributed new reagents/analytic tools; G.C., S.P., I.T., T.B., and A.F. analyzed data; and T.B. and A.F. wrote the paper.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0701466104/DC1.

§To whom correspondence may be addressed. E-mail: thomas.birchler{at}usz.ch or adriano.fontana{at}usz.ch

© 2007 by The National Academy of Sciences of the USA


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